Neuropathology of sporadic Parkinson disease before the appearance of parkinsonism: preclinical Parkinson disease

Abstract

Parkinson disease (PD) is no longer considered a complex motor disorder characterized by parkinsonism but rather a systemic disease with variegated non-motor deficits and neurological symptoms, including impaired olfaction, sleep disorders, gastrointestinal and urinary abnormalities and cardiovascular dysfunction, in addition to other symptoms and signs such as pain, depression and mood disorders. Many of these alterations appear before or in parallel with motor deficits and then worsen with disease progression. Although there is a close relation between motor symptoms and the presence of Lewy bodies (LBs) and neurites filled with abnormal α-synuclein, other neurological alterations are independent of LBs, thereby indicating that different mechanisms probably converge in the degenerative process. This review presents cardinal observations at very early stages of PD and provides personal experience based on the study of a consecutive series of brains with PD-related pathology and without parkinsonism, mainly cases categorized as stages 2-3 of Braak. Alterations in the substantia nigra, striatum and frontal cortex in pPD are here revised in detail. Early modifications in the substantia nigra at pre-motor stages of PD (preclinical PD: pPD) include abnormal small aggregates of α-synuclein which is phosphorylated, nitrated and oxidized, and which exhibits abnormal solubility and truncation. This occurs in association with a plethora of altered molecular events including increased oxidative stress, altered oxidative stress responses, altered balance of L-ferritin and H-ferritin, reduced expression of neuronal globin α and β chains in neurons with α-synuclein deposits, increased expression of endoplasmic reticulum stress markers, increased p62 and ubiquitin immunoreactivity in relation to α-synuclein deposits, and altered distribution of LC3 and other autophagosome/lysosome markers. In spite of the relatively small decrease in the number of dopaminergic neurons in the substantia nigra, which does not reach thresholds causative of parkinsonism, levels of tyrosine hydroxylase and cannabinoid 1 receptor are reduced, whereas levels of adenosine receptor 2A are increased in the caudate in pPD. Moreover, biochemical alterations are also present in the cerebral cortex (at least in the frontal cortex) in pPD including increased oxidative stress and oxidative damage to proteins α-synuclein, β-synuclein, superoxide dismutase 2, aldolase A, enolase 1, and glyceraldehyde dehydrogenase, among others, indicating post-translational modifications of PD-related proteins, and suggesting altered function of pathways involved in glycolysis and energy metabolism in the cerebral cortex in pPD. Current evidence suggests convergence of several altered metabolic pathways leading to chronic neuronal dysfunction, mainly manifested as sub-optimal energy metabolism, altered synaptic function, oxidative and endoplasmic reticulum stress damage and corresponding altered responses, among others. By understanding that these alterations occur at very ear...

Redox Proteomics in Selected Neurodegenerative Disorders: From Its Infancy to Future Applications

“…These aggregates are the major component of Lewy bodies located primarily in the putamen and substantia nigra, brain regions closely associated with motor movement. Recently, aggregates of oxidatively modified a-synuclein have been exhibited in the substantia nigra of patients before the appearance of PD (148). Consistent with increased aggregation of oxidized proteins, recent studies suggest asynuclein exists as a tetramer in PD rather than as a monomer or smaller aggregates in the normal state (30).…”

“…Oxidative damage is well known in PD brains (9,153,407) and has been associated with the overexpression of wild-type or mutant (-synuclein (295). Increased oxidative damage in several metabolic enzymes including glyceraldehyde 3-phosphate dehydrogenase, ALDO1, Eno1, and SOD have been observed in sporadic cases of PD, contributing to the hypothesis of reduced glucose metabolism in neurodegeneration (148). Similarly, iron imbalance is exhibited in PD and may be a consequence of the elevation of OS and changes in iron binding proteins as just discussed (12).…”

Melatonin attenuates MPTP-induced neurotoxicity via preventing CDK5-mediated autophagy and SNCA/α-synuclein aggregation

“…1,2 It is caused by the degeneration of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNc), which results in a decreased dopamine level in the striatum 3,4 and a formation of Lewy bodies that are predominantly composed of aggregated SNCA/a-synuclein. 5 However, molecular mechanisms underlying PD have not been fully understood.…”

Algorithms for the treatment of motor problems in Parkinson's disease

“…Parkinson's disease (PD) is a neurodegenerative disorder causing cell death in dopaminergic neurons in the Substantia nigra, but also in neurons in several other brain stem nuclei and in the cerebral cortex 1. Typically, the patients may have a combination of motor and non‐motor symptoms even when PD is first diagnosed 2.…”